What is the base catalyzed amide hydrolysis mechanism?

Question

Addison Armstrong · Accepted Answer

To make this very simple, I will try not to go into details and explain the basics.

Amides are molecules that can form from a carboxylic acid and an amine group. In our body, when two amino acids come together to react, they form an amide bond, releasing #"H"_2"O"# in the process. This type of bond is also called a peptide bond.

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#color(white)(aaaaaaaaaaaaaaaaaa)# Mechanism

#color(purple)(1.)#

To begin, we know that in the first step, a strong base is going to be used like #"NaOH"#, where the #color(blue)("OH"^(-)# will act as the nucleophile and attack the electrophile, the partial positive carbon of the carbonyl group.

Now, when the bond forms between the #"oxygen"# of the #"OH"^-# group and the carbon, the #pi# #"bond"# of the carbonyl is broken and the electrons are pushed toward oxygen, leaving it with a negative #-1# charge.

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#color(blue)("Oxygen will try to remove this negative charge by reforming")# #color(blue)("a double bond with the carbon")#. But since we know that the #"carbon"# atom cannot form more than 4 bonds, the bond between it and the amine's #"nitrogen"# has to be broken. #color(blue)("The electrons will be pushed onto the nitrogen of the amine and the")# #color(blue)("amine will act as the leaving group (a poor one at that)")#

*The reason the amine is a poor leaving group is because the amine is a strong base, and strong bases are very unstable. Leaving groups are based off their stability in solution, like the halides, tosylate, #"H"_2"O"#

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#color(blue)("Here, the NH"_2^(-) "will act as a base and pluck off the H from the carboxylic")# #color(blue)("acid - type of acid-base reaction.")# When this happens, a #"carboxylate anion"# forms and #"NH"_3#.

Skylar Alexander · Answer

undefined The base-catalyzed amide hydrolysis mechanism involves the nucleophilic attack of the amide nitrogen by a hydroxide ion, followed by tetrahedral intermediate formation, collapse of the intermediate to yield a carboxylate ion and an amine, and finally, protonation of the carboxylate ion to produce the carboxylic acid.

Isaac Aronson · Answer

undefined The base-catalyzed amide hydrolysis mechanism typically involves the following steps:

1. **Nucleophilic Attack**: A hydroxide ion (OH−) acts as a nucleophile and attacks the carbonyl carbon of the amide, forming a tetrahedral intermediate. This step is facilitated because the carbonyl carbon is electrophilic.

2. **Intermediate Formation**: The nucleophilic attack results in the formation of a tetrahedral intermediate. The negative charge is usually delocalized to the oxygen atom, stabilizing the intermediate.

3. **Proton Transfer**: In some mechanisms, a proton (H+) transfer occurs, either in the same step as the nucleophilic attack or in a separate step. This can involve the migration of a proton from the nitrogen to the oxygen atom within the intermediate or the involvement of water or another base in the reaction mixture.

4. **Collapse of the Tetrahedral Intermediate**: The tetrahedral intermediate collapses, leading to the expulsion of the amine group. This step reforms the carbonyl group and releases the amine or ammonia.

5. **Protonation and Recovery of the Carboxylate Anion**: The final product of the reaction is a carboxylate anion and an amine or ammonia. If the reaction medium contains a weak acid or if water acts as a proton donor, the carboxylate can be protonated to form a carboxylic acid.

The overall result is the conversion of an amide into a carboxylate anion and an amine or ammonia. The reaction is facilitated by base, which acts to deprotonate water, generating the hydroxide ion that initiates the nucleophilic attack. This mechanism contrasts with acid-catalyzed hydrolysis, where the first step involves protonation of the carbonyl oxygen, making the carbon more electrophilic and susceptible to attack by water.